Atherosclerosis defined as a chronic inflammatory disease of large arteries is the primary cause of heart diseases and stroke. Inflammation is a central process in all stages of atherosclerosis. The formation of early atherosclerotic lesions involves the recruitment and activation of immune cells, particularly macrophages. The functions of macrophages play a critical role in the development of atherosclerosis. Although studies have yielded much information about the role of macrophages in atherosclerosis, the molecular basis of macrophage functions, such as the regulatory expression of proinflammatory genes, uptake of oxidized low-density lipoprotein (oxLDL) to form foam cells and apoptosis, remains to be fully understood. 2-5A dependent RNase L (RNase L) is one of the key enzymes involved in the interferon (IFN) functions against viral infection and cell proliferation. Furthermore, the role of RNase L in the regulation of gene expression and cell apoptosis has been well established in the last decade. In this proposed study, we hypothesize that RNase L regulates the macrophage expression of proinflammatory genes induced by different atherogenic stimuli, and modulates macrophage functions, resulting in the promotion of inflammatory response and lesion formation in the process of atherosclerotic development. This hypothesis is based on our preliminary studies that RNase L functions as a regulator for the expression of cyclooxygenase-2 (Cox-2) and peroxisome proliferators-activated receptorgamma (PPAR-y,) in mouse embryonic fibroblasts (MEF). Both genes are involved in the inflammatory process during the development of atherosclerosis. RNase L also mediates bone marrow-derived macrophage apoptosis after withdrawal of M-CSF. To test our hypothesis, the following aims are proposed: (1) To investigate the effect of RNase L on the expression of proinflammatory genes, we will examine the expression of Cox-2, PPAR-y and inducible nitric oxide synthase (iNOS) in RNase L +/+ and -/- bone marrow-derived macrophages stimulated by lipopolysaccharide (LPS), polyinosinic-polycytidylic (Poly I:C) and oxLDL; (2) To determine the role of RNase L in mediating the development of atherosclerotic lesions, we will first determine the role of RNase L in the formation of foam cells and macrophage apoptosis. We will also determine the vulnerability of RNase L null and wild type mice in the development of atherosclerosis. This study will provide new insights into the molecular mechanism of atherosclerotic development.